Transdermal Drug Delivery Device

ABSTRACT

A transdermal drug delivery device is disclosed that may comprise a housing including an upper housing portion and a lower housing portion. The lower housing portion may define a bottom surface including skin attachment means for releaseably attaching the lower housing portion to skin of a user. The upper housing portion may at least partially surround a central region of the device. The device may also include a microneedle assembly and a reservoir disposed within the central region. The reservoir may be in fluid communication with the microneedle assembly. Additionally, the device may include a pushing element disposed above the microneedle assembly within the central region. The pushing element may be configured to provide a continuous bilateral force having a downward component transmitted through the microneedle assembly and an upward component transmitted through the skin attachment means.

FIELD OF THE INVENTION

The present subject matter relates generally to devices for deliveringdrug formulations to a patient through the skin utilizing a microneedleassembly.

BACKGROUND OF THE INVENTION

Numerous devices have previously been developed for the transdermaldelivery of drugs and other medicinal compounds utilizing microneedleassemblies. Microneedles have the advantage of causing less pain to thepatient as compared to larger conventional needles. In addition,conventional subcutaneous (often intra-muscular) delivery of drugs via aneedle acts to deliver large amounts of a drug at one time, therebyoften creating a spike in the bioavailability of the drug. For drugswith certain metabolic profiles this is not a significant problem.However, many drugs benefit from having a steady state concentration inthe patient's blood stream, a well-known example of such a drug isinsulin. Transdermal drug delivery devices are technically capable ofslowly administering drugs at a constant rate over an extended period oftime. Thus, transdermal drug delivery devices offer several advantagesrelative to conventional subcutaneous drug delivery methods.

However, existing transdermal drug delivery devices often fail toconsistently deliver all of the drug beneath the stratum corneum layerof the skin so that it can be absorbed into the body. In this regard,due to the small size of the needles, often times all or a portion ofthe drug is delivered only onto the top of the skin or into the stratumcorneum layer where the drug cannot be absorbed into the body of thepatient. This can happen for various reasons. For example, the needledepth may slightly retract from the desired insertion depth such as dueto the inconsistent application of force on the needles or the naturalelasticity of the skin acts to push the needles outwardly afterinsertion. Further complicating transdermal delivery with such smallneedles is that the skin may form such a complete juncture with theneedle that the drug flows upwardly along the needle towards the pointof insertion and away from the cellular layers capable of absorbing thedrug into the body.

Accordingly, there remains a need for a transdermal drug delivery devicehaving an improved ability to consistently and effectively deliver adrug formulation through a patient's skin.

BRIEF DESCRIPTION OF THE INVENTION

Aspects and advantages of the invention will be set forth in part in thefollowing description, or may be obvious from the description, or may belearned through practice of the invention.

In one aspect, the present subject matter is directed to a transdermaldrug delivery device. The device may comprise a housing including anupper housing portion and a lower housing portion. The lower housingportion may define a bottom surface including skin attachment means forreleaseably attaching the lower housing portion to skin of a user. Theupper housing portion may at least partially surround a central regionof the device. The device may also include a microneedle assembly and areservoir disposed within the central region. The reservoir may be influid communication with the microneedle assembly. Additionally, thedevice may include a pushing element disposed above the microneedleassembly within the central region. The pushing element may beconfigured to provide a continuous bilateral force having a downwardcomponent transmitted through the microneedle assembly and an upwardcomponent transmitted through the skin attachment means.

In another aspect, the present subject matter is directed to atransdermal drug delivery device. The device may include an upperhousing attached to a lower housing defining a cavity. The lower housingmay define a bottom surface including skin attachment means forreleasably attaching the lower housing to skin of a user. The lowerhousing may also define an opening and may surround a microneedleassembly. The device may be configured such that the lower housing isdissociated from the microneedle assembly. In addition, the device mayinclude a reservoir disposed within the cavity that is in fluidcommunication with the microneedle assembly. Moreover, the device mayinclude a pushing element disposed within the cavity between themicroneedle assembly and the upper housing. The pushing element may beconfigured so as to be dissociated from the lower housing and mayprovide (i) a continuous force having a downward component, dissociatedfrom the upper and lower housings, transmitted via the microneedleassembly towards the skin of a user, (ii) a continuous force having anupward component, dissociated from the microneedle assembly, transmittedto the lower housing.

In a further aspect, the present subject matter is directed to a methodfor transdermally delivering a drug formulation. The method maygenerally include positioning a transdermal drug delivery deviceadjacent to skin, attaching a housing of the device to the skin via askin attachment means, applying, with a pushing element, a continuousbilateral force having a downward component transmitted through amicroneedle assembly of the device and an upward component transmittedthrough the skin attachment means delivering the drug formulation fromthrough the microneedle assembly and into or through the skin.

These and other features, aspects and advantages of the presentinvention will become better understood with reference to the followingdescription and appended claims. The accompanying drawings, which areincorporated in and constitute a part of this specification, illustrateembodiments of the invention and, together with the description, serveto explain the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

A full and enabling disclosure of the present invention directed to oneof ordinary skill in the art, is set forth in the specification, whichmakes reference to the appended figures, in which:

FIG. 1 illustrates an assembled, perspective view of one embodiment of atransdermal drug delivery device in accordance with aspects of thepresent subject matter;

FIG. 2 illustrates a cross-sectional view of the device shown in FIG. 1taken about line 2-2, particularly illustrating various components ofthe device in an un-actuated position;

FIG. 3 illustrates another cross-sectional view of the device shown inFIG. 1 taken about line 2-2, particularly illustrating variouscomponents of the device in an actuated position;

FIG. 4 illustrates an exploded, perspective view of the device shown inFIGS. 1-3;

FIG. 5 illustrates an assembled, perspective view of another embodimentof a transdermal drug delivery device in accordance with aspects of thepresent subject matter;

FIG. 6 illustrates a cross-sectional view of the device shown in FIG. 5taken about line 6-6, particularly illustrating various components ofthe device in an un-actuated position;

FIG. 7 illustrates another cross-sectional view of the device shown inFIG. 6, particularly illustrating various components of the device in anactuated position;

FIG. 8 illustrates an exploded, perspective view of the device shown inFIGS. 5-7;

FIG. 9 illustrates a cross-sectional view of a bilateral pushing elementof the device shown in FIGS. 5-8, particularly illustrating thebilateral pushing element in an un-actuated or un-expanded position;

FIG. 10 illustrates another cross-sectional view of the bilateralpushing element of the device shown in FIGS. 5-8, particularlyillustrating the bilateral pushing element in an actuated or expandedposition; and

FIG. 11 illustrates a close-up, partial view of one embodiment of amicroneedle assembly configuration suitable for use with the disclosedtransdermal drug delivery devices.

DETAILED DESCRIPTION OF THE INVENTION

Reference now will be made in detail to embodiments of the invention,one or more examples of which are illustrated in the drawings. Eachexample is provided by way of explanation of the invention, notlimitation of the invention. In fact, it will be apparent to thoseskilled in the art that various modifications and variations can be madein the present invention without departing from the scope or spirit ofthe invention. For instance, features illustrated or described as partof one embodiment can be used with another embodiment to yield a stillfurther embodiment. Thus, it is intended that the present inventioncovers such modifications and variations as come within the scope of theappended claims and their equivalents.

In general, the present subject matter is directed to a transdermal drugdelivery device configured to deliver a drug formulation into and/orthrough a user's skin. The device may generally include a housingconfigured to encase or surround various components of the device, withat least a portion of the housing being configured to be attached to theuser's skin. The device may also include a reservoir in fluidcommunication with a microneedle assembly. The reservoir may generallybe configured to retain a drug formulation for subsequent deliverythrough the user's skin via the microneedle assembly. In addition, thedevice may include a pushing element configured to apply a continuousbilateral force through the device. Specifically, in severalembodiments, the pushing element may be configured to apply a continuousdownward force through the microneedle assembly to push the microneedlesof the assembly into the user's skin. Simultaneously, the pushingelement may be configured to apply a continuous upward force against thehousing that is transmitted through the housing to the user's skin (viaa suitable skin attachment means disposed between the housing and theskin), thereby providing a tensioning force that tightens the user'sskin around the microneedle assembly to enhance insertion andmaintenance of the microneedles into/within the skin.

Referring now to the drawings, FIGS. 1-4 illustrate several views of oneembodiment of a transdermal drug delivery device 10 in accordance withaspects of the present subject matter. As shown, the device 10 mayinclude an outer housing 12 configured to at least partially surroundand/or encase the various components of the device 10. In general, thehousing 12 may include an upper housing portion 14 and a lower housingportion 16 formed integrally with and/or extending from the upperhousing portion 14. The upper housing portion 14 may generally beconfigured to define an open volume for housing the various devicecomponents. For example, as shown FIGS. 2 and 3, when the device 10 isplaced onto the user's skin 18, an open volume may be defined betweenthe user's skin 18 and the upper housing portion 14 within which thedevice components may be contained. It should be appreciated that theupper housing portion 14 may generally be configured to define anysuitable shape. For instance, as shown in the illustrated embodiment,the upper housing portion 14 defines a semi-circular or dome shape.However, in other embodiments, the upper housing portion 14 may have anyother suitable shape that defines an open volume for housing the variouscomponents of the device 10.

The lower housing portion 16 of the housing 12 may generally beconfigured to be positioned adjacent to the user's skin when the device10 is in use. For example, as shown in the illustrated embodiment, thelower housing portion 16 may be configured as a flange or projectionextending outwardly from the bottom periphery of the upper housingportion 14 such that a bottom surface 20 of the lower housing portion 16may extend directly adjacent to the user's skin 18. Additionally, inseveral embodiments, the lower housing portion 16 may be configured tobe attached to the user's skin 18 using any suitable skin attachmentmeans. For example, in one embodiment, an adhesive layer 22 may beapplied to the bottom surface 20 of the lower housing portion 16. Assuch, when the device 10 is placed onto the user's skin 18, the housing12 may be attached to the skin 18 via the adhesive layer 20. However, inother embodiments, any other suitable skin attachment means known in theart may be utilized to attach the housing 12 to the user's skin 18.

Additionally, as particularly shown in FIGS. 2 and 3, different zones orregions of the device 10 may be defined by and/or within the housing 12.For example, the device 10 may include a central region 30 definedaround its center line 31. The device 10 may also include an outerregion 32 generally defined around the device periphery at the locationat which the device 10 is attached to the user's skin 18. For example,as shown in FIGS. 2 and 3, the outer region 32 may be defined at theinterface between the bottom surface 20 of the lower housing portion 18and the adhesive layer 22 securing the housing 12 to the user's skin 18.Moreover, the device 10 may include an intermediate region 34 extendingbetween and separating the central and outer regions 30, 32.

In several embodiments, the device 10 may include one or more componentsat least partially disposed within the central region 30. For example,as shown in the illustrated embodiment, the device 10 includes amicroneedle assembly 36, a reservoir 38 and a bilateral pushing element40 vertically aligned within the central region 30, with the footprintof such components generally defining the outer perimeter of the centralregion 30. As will be described below, the pushing element 40 may beconfigured to apply a downward force through the central region 30 inorder to press the microneedle assembly 36 into the user's skin 18. Inaddition, the pushing element 40 may also be configured to apply anupward force through the central region 30 that is transmitted throughthe housing 12 to the outer region 32 of the device 10, therebyproviding an upward force against the user's skin 18 via the adhesivelayer 22.

In general, the microneedle assembly 36 of the device 10 may have anysuitable configuration known in the art for delivering a fluidic drugformulation into and/or through the user's skin 18, such as by beingconfigured to include a plurality of microneedles extending outwardlyfrom a suitable substrate or support. For example, a partial,cross-sectional view of one embodiment of a suitable microneedleassembly configuration is illustrated in FIG. 11. As shown, themicroneedle assembly 36 may include a support 42 defining a top surface44 and a bottom surface 46 and a plurality of microneedles 48 extendingoutwardly from the bottom surface 46. The support 42 may generally beconstructed from a rigid, semi-rigid or flexible sheet of material, suchas a metal material, a ceramic material, a plastic material and/or anyother suitable material. In addition, the support 42 may define one ormore apertures between its top and bottom surfaces 44, 46 to permit thedrug formulation to flow therebetween. For example, as shown in FIG. 11,a single aperture 50 may be defined in the support 42 at the location ofeach microneedle 48 to permit the drug formulation to be delivered fromthe top surface 44 to such microneedle 48. However, in otherembodiments, the support 42 may define any other suitable number ofapertures 50 positioned at and/or spaced apart from the location of eachmicroneedle 48

Additionally, as shown in FIG. 11, each microneedle 48 of themicroneedle assembly 36 may generally be configured to define a piercingor needle-like shape (e.g., a conical or pyramidal shape or acylindrical shape transitioning to a conical or pyramidal shape)extending between a base 52 positioned adjacent to and/or extending fromthe bottom surface 46 of the support 42 and a tip 54 disposed oppositethe base 52. As is generally understood, the tip 52 may correspond tothe point of each microneedle 48 that is disposed furthest away from thesupport 42 and may define the smallest dimension of each microneedle 48.Additionally, each microneedle 48 may generally define any suitablelength 51 between its base 52 and its tip 52 that is sufficient to allowthe microneedles 48 to penetrate the stratum corneum and pass into theepidermis. In several embodiments, it may be desirable to limit thelength 51 of the microneedles 48 such that they do not penetrate throughthe inner surface of the epidermis and into the dermis; such embodimentsadvantageously help minimize pain for the patient receiving the drugformulation. For example, in one embodiment, each microneedle 48 maydefine a length 51 of less than about 1000 micrometers (um), such asless than about 800 um, or less than about 750 um or less than about 500um and any other subranges therebetween. In a particular embodiment, thelength 51 may range from about 25 um to about 1000 um, such as fromabout 100 um to about 1000 um or from about 200 um to about 1000 um andany other subranges therebetween.

It should be appreciated that the length 51 of the microneedles 48 mayvary depending on the location at which the disclosed device is beingused on a user. For example, the length of the microneedles 48 for adevice to be used on a user's leg may differ substantially from thelength of the microneedles 48 for a device to be used on a user's arm.

Moreover, each microneedle 48 may generally define any suitable aspectratio (i.e., the length 51 over a cross-sectional dimension 53 of eachmicroneedle 48). However, in certain embodiments, the aspect ratio maybe greater than 2, such as greater than 3 or greater than 4. It shouldbe appreciated that, in instances in which the cross-sectional dimension53 (e.g., width, diameter, etc.) varies over the length of eachmicroneedle 26 (e.g., as shown in FIG. 11), the aspect ratio may bedetermined based on the average cross-sectional dimension 53.

Further, each microneedle 48 may define one or more channels 56 in fluidcommunication with the apertures 50 defined in the support 42. Ingeneral, the channels 56 may be defined at any suitable location onand/or within each microneedle 48. For example, as shown in FIG. 11, inone embodiment, the channels 56 may be defined along an exterior surfaceof each microneedle 48. In another embodiment, the channels 56 may bedefined through the interior of the microneedles 48 such that eachmicroneedle 48 forms a hollow shaft. Regardless, the channels 56 maygenerally be configured to form a pathway that enables the drugformulation to flow from the top surface 44 of the support 42, throughthe apertures 50 and into the channels 56, at which point the drugformulation may be delivered into and/or through the user's skin 18.

It should be appreciated that the channels 56 may be configured todefine any suitable cross-sectional shape. For example, in oneembodiment, each channel 56 may define a semi-circular or circularshape. In another embodiment, each channel 56 may define a non-circularshape, such as a “v” shape or any other suitable cross-sectional shape.

In several embodiments, the dimensions of the channels 56 defined by themicroneedles 48 may be specifically selected to induce a capillary flowof the drug formulation. As is generally understood, capillary flowoccurs when the adhesive forces of a fluid to the walls of a channel aregreater than the cohesive forces between the liquid molecules.Specifically, the capillary pressure within a channel is inverselyproportional to the cross-sectional dimension of the channel anddirectly proportional to the surface energy of the subject fluid,multiplied by the cosine of the contact angle of the fluid at theinterface defined between the fluid and the channel. Thus, to facilitatecapillary flow of the drug formulation through the microneedle assembly36, the cross-sectional dimension 58 (FIG. 11) of the channel(s) 56(e.g., the diameter, width, etc.) may be selectively controlled, withsmaller dimensions generally resulting in higher capillary pressures.For example, in several embodiments, the cross-sectional dimension 58may be selected so that the cross-sectional area of each channel 56ranges from about 1,000 square microns (um²) to about 125,000 um², suchas from about 1,250 um² to about 60,000 um² or from about 6,000 um² toabout 20,000 um² and any other subranges therebetween.

It should be appreciated that FIG. 11 only illustrates a portion of asuitable microneedle assembly configuration and, thus, the microneedleassembly 36 used within the device 10 may generally include any numberof microneedles 48 extending from its support 42. For example, in oneembodiment, the actual number of microneedles 48 included within themicroneedle assembly 36 may range from about 10 microneedles per squarecentimeter (cm²) to about 1,500 microneedles per cm², such as from about50 microneedles per cm², to about 1250 microneedles per cm² or fromabout 100 microneedles per cm² to about 500 microneedles per cm² and anyother subranges therebetween.

It should also be appreciated that the microneedles 48 may generally bearranged on the support 42 in a variety of different patterns, and suchpatterns may be designed for any particular use. For example, in oneembodiment, the microneedles 48 may be spaced apart in a uniform manner,such as in a rectangular or square grid or in concentric circles. Insuch an embodiment, the spacing of the microneedles 48 may generallydepend on numerous factors, including, but not limited to, the lengthand width of the microneedles 48, as well as the amount and type of drugformulation that is intended to be delivered through the microneedles48. By way of non-limiting example, micro-needle arrays suitable for usewith the present invention include those described in WO2012/020332 toRoss; WO2001/0270221 to Ross; and WO2011/070457 to Ross.

Referring back to FIGS. 1-4, as indicated above, the disclosed device 10may also include a reservoir 38 in fluid communication with themicroneedle assembly 36. Specifically, as shown in FIGS. 2 and 3, thereservoir 38 may be positioned above the microneedle assembly 36 withinthe central region 30 of the device 10. In several embodiments, thereservoir 38 may be configured to be attached to a portion of themicroneedle assembly 36. For example, as shown in FIGS. 2 and 3, anadhesive layer 60 may be disposed between a bottom surface 62 of thereservoir 38 and the top surface of the microneedle assembly 36 (i.e.,the top surface 44 of the support 42) in order to secure the microneedleassembly 36 to the reservoir 38.

In general, the reservoir 38 may have any suitable structure and/or maybe formed from any suitable material that permits the reservoir 38 toinitially retain the drug formulation prior to its subsequent deliveryinto the microneedle assembly 36. Thus, it should be appreciated that,as used herein, the term “reservoir” may generally refer to any suitabledesignated area or chamber within the device 10 that is configured toretain a fluidic drug formulation. For example, as shown in theillustrated embodiment, the reservoir 38 may be configured as a rigid orsemi-rigid member defining an open volume or cavity 64 for retaining thedrug formulation. However, in other embodiments, the reservoir 38 mayhave any other suitable configuration. For example, in anotherembodiment, the reservoir 38 may be configured as a flexible bladder. Ina further embodiment, the reservoir 38 may be configured as a solidcontainer or matrix through which the drug formulation is capable ofbeing directed, such as a permeable, semi-permeable or microporous solidmatrix. In still a further embodiment, the reservoir 38 may comprise aflexible bladder contained within or shielded by a rigid member.

It should be appreciated that any suitable drug formulation(s) may beretained within reservoir 38 and subsequently delivered through theuser's skin 18 via the microneedle assembly 36. As used herein, the term“drug formulation” is used in its broadest sense and may include, but isnot limited to, any drug (e.g., a drug in neat form) and/or anysolution, emulsion, suspension and/or the like containing a drug(s).Similarly, the term “drug” is used in its broadest sense and includesany compound having or perceived to have a medicinal benefit, which mayinclude both regulated and unregulated compounds. For example, suitabletypes of drugs may include, but are not limited to, biologics, smallmolecule agents, vaccines, proteinaceous compounds, anti-infectionagents, hormones, compounds regulating cardiac action or blood flow,pain control agents and so forth. One of ordinary skill in the artshould readily appreciate that various ingredients may be combinedtogether in any suitable manner so as to produce a compound having orperceived to have a medicinal benefit.

It should also be appreciated that the drug formulation may be suppliedto the reservoir 38 in a variety of different ways. For example, inseveral embodiments, the drug formulation may be supplied via an inletchannel 66 defined through a portion of the reservoir 38. In such anembodiment, a suitable conduit, port or tube 68 (e.g., a micro-bore tubeor any other suitable flexible tube) may be configured to be receivedwithin the inlet channel 66 and may be in fluid communication with asuitable drug source (e.g., a syringe containing the drug formulation)such that the drug formulation may be directed through the inlet channel66 and into the reservoir 38. In other embodiments, the drug formulationmay be supplied to the reservoir 38 using any other suitablemeans/method. For example, the reservoir 38 may be configured to bepre-filled or pre-charged prior to being assembled into the device 10.

Additionally, as particularly shown in FIG. 4, the device 10 may alsoinclude a rate control membrane 70 disposed between the reservoir 38 andthe microneedle assembly 36. In general, the rate control membrane 70may be configured to slow down or otherwise control the flow rate of thedrug formulation as it is released from the reservoir 38. The particularmaterials, thickness, etc. of the rate control membrane 70 may, ofcourse, vary based on multiple factors, such as the viscosity of thedrug formulation, the desired delivery time, etc.

In several embodiments, the rate control membrane 70 may be fabricatedfrom any suitable permeable, semi-permeable or microporous material(s).For example, in several embodiments, the material used to form the ratecontrol membrane 70 may have an average pore size of from about 0.01micron to about 1000 microns, such as from about 1 micron to about 500microns or from about 20 microns to about 200 microns and any othersubranges therebetween. Additionally, in a particular embodiment, thematerial used to form the rate control membrane 70 may have an averagepore size ranging from about 0.01 micron to about 1 micron, such as fromabout 0.1 micron to about 0.9 micron or from about 0.25 micron to about0.75 micron and any other subranges therebetween, Suitable membranematerials include, for instance, fibrous webs (e.g., woven or nonwoven),apertured films, foams, sponges, etc., which are formed from polymerssuch as polyethylene, polypropylene, polyvinyl acetate, ethylene n-butylacetate and ethylene vinyl acetate copolymers.

Referring still to FIGS. 1-4, the device 10 may also include a plunger72 positioned directly above of the reservoir 38. In general, theplunger 72 may be configured to be moved relative to the housing 12 asthe various components contained within the housing 12 are moved betweenun-actuated position (FIG. 2), wherein the bottom of the microneedleassembly 36 is generally aligned with or recessed relative to the bottomsurface 20 of the lower housing portion 16 and an actuated position(FIG. 3), wherein the microneedle assembly 36 extends outward beyond thebottom surface 20 of the lower housing portion 16, thereby allowing themicroneedles 48 of the assembly 36 to penetrate the user's skin 18. Asshown in FIGS. 2-4, in one embodiment, the plunger 72 may generallyinclude a cylindrical top portion 74 configured to be slidably receivedwithin a corresponding opening 76 defined in the housing 12 and aflattened bottom portion 78 configured to engage or otherwise bepositioned directly adjacent to the reservoir 38. In such an embodiment,when the plunger 72 is moved downward relative to the housing 12, thebottom portion 78 of the plunger 72 may apply a force against thereservoir 38 that pushes the microneedle assembly 36 downward into theuser's skin 18.

Additionally, as indicated above, the disclosed device 10 may alsoinclude a bilateral pushing element 40 disposed within the centralregion 30 of the device 10. In general, the pushing element 40 may beany suitable biasing mechanism and/or force application means that isconfigured to apply a continuous bilateral force (having both a downwardcomponent and an upward component) through the device 10 to the user'sskin 18. For example, as shown in the illustrated embodiment, thepushing element 40 comprises a spring compressed between the housing 12and the plunger 72. Thus, when the device 10 is moved to the actuatedposition during use (FIG. 3), the spring may be configured to apply acontinuous bilateral force against the housing 12 and the plunger 72that is transmitted through the device 10 to the user's skin 18.Specifically, the downward component of the force (indicated by arrows84 in FIG. 3) may be transmitted downward through the central region 30of the device 10 (i.e., through the plunger 72 and the reservoir 38) tothe microneedle assembly 36 such that the microneedles 48 of theassembly 36 are pressed into and maintained within the user's skin 18.Similarly, the upward component of the force (indicated by arrows 86 inFIG. 3) may be transmitted upward through the central region 30 of thedevice 30 to the housing 12, thereby pushing housing 12 away from theuser's skin 18. However, since the housing 12 is attached to the user'sskin 18 around its outer periphery (i.e., at the outer region 32 of thedevice 10), such upward force may generally be transmitted through thehousing 12 and the adhesive layer 22 so as to provide an upward,tensioning force against the user's skin 18. Thus, as the microneedles48 are pushed downward into the user's skin 18, the user's skin 18 maysimultaneously be pulled upwards around the periphery of the device 10,thereby tightening the skin 18 around the microneedle assembly 36 andenhancing the ease at which the microneedles 48 may be inserted into andmaintained within the user's skin 18.

In several embodiments, the device 10 may also include a lockingmechanism configured to maintain the device components in theun-actuated position when the device 10 is not use. For example, asshown in FIG. 1, a lock pin 80 may be configured to extend through anopening 82 defined in the plunger 72 so as to engage opposing sides ofthe upper housing portion 14, thereby maintaining the spring in acompressed or un-actuated state. However, when the lock pin 80 isremoved, the spring may be decompressed so that the continuous bilateralforce is transmitted through the device 10 to the user's skin 18. Inalternative embodiments, the locking mechanism may have any othersuitable configuration and/or may be associated with any other suitablecomponent of the device 10.

It should be appreciated that, as an alternative to the spring/lock pin80 arrangement, the plunger 72 may be moved between the un-actuated andactuated positions using any other suitable arrangement and/orconfiguration known in the art.

For example, in another embodiment, the top portion 74 of the plunger 72extending outwardly beyond the top of the upper housing portion 14 maybe used as a push-button to manually push the plunger 72 downward intothe actuated position. In such an embodiment, the bottom of the spring40 may, for example, be coupled to the plunger 72 so that the spring 40biases the plunger 72 into the un-actuated position.

It should be noted that, since the reservoir 38 may be configured as arigid or semi-rigid member in the illustrated embodiment, the forceapplied by the pushing element 40 is transmitted through the body of thereservoir 38 instead of being transmitted to the drug formulationitself. Accordingly, the microneedles 48 may be pressed into the user'sskin 18 without increasing the pressure of the drug formulation orotherwise applying a significant downward force upon the drugformulation. Stated differently, the pushing element 40, when actuatedand applying a downward force on the microneedle assembly 36, does notpressurize the fluidized drug passing out of the device and into theskin through the microneedle channels 56.

Referring now to FIGS. 5-10, several views of another embodiment of atransdermal drug delivery device 110 are illustrated in accordance withaspects of the present subject matter. As shown, the device 110 mayinclude an outer housing 112 configured to at least partially surroundand/or encase the various components of the device 110. In general, thehousing 112 may include an upper housing portion 114 and a lower housingportion 116. However, unlike the housing 12 described above withreference to FIGS. 1-4, the upper housing portion 114 and the lowerhousing portion 116 may comprise separate components configured to beseparately attached to one another. For example, as shown in FIGS. 6-8,in one embodiment, a bottom peripheral surface 117 of the upper housingportion 114 may be configured to be secured to a top surface 118 of thelower housing portion 116 using an adhesive, thermal bonding/welding orany other suitable attachment means.

In general, the upper housing portion 114 may be configured as an outershell defining an open volume for housing the various device components.For example, as shown FIGS. 6 and 7, when the housing 112 is assembled,an open volume may be defined between the upper housing portion 114 andthe lower housing portion 116 within which the device components may beat least partially contained. It should be appreciated that the upperhousing portion 114 may be configured to define any suitable shape. Forinstance, as shown in the illustrated embodiment, the upper housingportion 114 generally defines a semicircular or dome shape. However, inother embodiments, the upper housing portion 114 may have any othersuitable shape that defines an open volume for housing the variouscomponents of the device 10. The lower housing portion 116 of thehousing 112 may generally be configured to be positioned adjacent to theuser's skin 18 when the device 110 is in use. For example, as shown inthe illustrated embodiment, the lower housing portion 116 may comprise aflat panel configured to extend both inwardly and outwardly from thebottom peripheral surface 117 of the upper housing portion 114 such thata bottom surface 120 of the lower housing portion 116 extends directlyadjacent to the user's skin 18. Additionally, as shown in FIG. 8, thelower housing portion 116 may define a central opening 121 through whichthe user's skin 18 may be accessed. For instance, as will be describedbelow, a microneedle assembly 136 of the device 110 may be configured toextend through the opening 121 to allow such assembly to penetrate theuser's skin 18.

Moreover, in several embodiments, the lower housing portion 116 may beconfigured to be attached to the user's skin 18 using a suitable skinattachment means. For example, in one embodiment, an adhesive 122 may beapplied to the bottom surface 120 of the lower housing portion 116. Assuch, when the device 10 is placed onto the user's skin 18, the housing112 may be attached to the skin 18 via the adhesive layer 122. However,in other embodiments, any other suitable skin attachment means known inthe art may be utilized to attach the housing 112 to the user's skin 18.

It should be appreciated that, in several embodiments, both the upperhousing portion 114 and the lower housing portion 116 may be formed froma relatively flexible material, such as a flexible polymer material, toallow the housing 112 to generally conform the shape of the user's bodyand/or to facilitate proper adhesion to the skin 18. In suchembodiments, the device 110 may also include a rigid support member 124extending between the upper and lower housing portions 114, 116 so as toprovide structural support to the device 110. For example, as shown inFIG. 8, the support member 124 may define a relatively flat platform125. The flat underside of the platform 125 may, in one aspect, providea flat or substantially flat surface relative to the bilateral pushingelement such that the bilateral pushing element can achieve a reliableand/or even engagement with this surface when actuated. In addition, thesupport member 124 may further include an outward projection 126extending upward from the platform 125. Additionally, as shown in FIG.8, the upper housing portion 114 may be configured to define a supportopening 128 configured to receive the projection 126. Thus, when theprojection 126 is received within the support opening 128, at least aportion of the upper housing portion 114 may contact against and besupported by the platform 125. Moreover, the top of the support member124 may also provide a load-bearing surface through which a force may beapplied by the user when attaching the device 110 to the user's skin 18.

Similar to the embodiment described above with reference to FIGS. 1-4,the device 110 may include different zones or regions defined by and/orwithin the housing 112. For example, as shown in FIGS. 6 and 7, thedevice 110 may include a central region 130 defined around its centerline 131. The device 110 may also include an outer region 132 generallydefined at the location at which the device 110 is attached to theuser's skin 18. For example, as shown in FIGS. 6 and 7, the outer region132 may be defined at the interface between the bottom surface 120 ofthe lower housing portion 116 and the adhesive layer 122. Moreover, thedevice 110 may also include an intermediate region 134 extending betweenand separating the central and outer regions 130, 132.

In several embodiments, the device 110 may include one or morecomponents at least partially disposed within the central region 130.For example, as shown in the illustrated embodiment, the device 110 mayinclude a microneedle assembly 136, a reservoir 138 and a bilateralpushing element 140 vertically aligned within the central region 130,with the footprint of the microneedle assembly 136 and the pushingelement 140 generally defining the outer perimeter of the central region130. As will be described below, the pushing element 140 may beconfigured to apply a downward force through the central region 130 inorder to press the microneedle assembly 136 into the user's skin 18. Inaddition, the pushing element 140 may also be configured to apply anupward force through the central region 130 that is transmitted throughthe housing 112 to the outer region 132 of the device 110, therebyproviding an upward force against the user's skin 18 via the adhesivelayer 122.

In general, the microneedle assembly 136 may be configured the same asor similar to the microneedle assembly 36 described above. For example,as shown in FIG. 11, in several embodiments, the microneedle assembly136 may include a support 42 having a top surface 44 and a bottomsurface 46 and defining a plurality of apertures 50 between the top andbottom surfaces 44, 46. In addition, the microneedle assembly 136 mayalso include a plurality of microneedles 48 extending outwardly from thebottom surface 46. As described above, each microneedle 48 may define achannel(s) 56 in fluid communication with the apertures 50. As such, thedrug formulation contained within the device 110 may be directed fromthe top surface 44 of the support 42 through the apertures 50 and intothe microneedles 48 for subsequent delivery to the user's skin 18.

Additionally, similar to the embodiment described above, the reservoir138 of the device 110 may generally be configured as any suitabledesignated area or chamber within which the drug formulation may beinitially retained prior to the subsequent delivery of the formulationto the microneedle assembly 136. For example, as shown in theillustrated embodiment, the reservoir 138 may be configured as aflexible bladder. Specifically, as shown in FIG. 8, the reservoir 138may include a flexible top layer 142 and a flexible bottom layer 144,with the top and bottom layers 142, 144 being configured to be securedto one another around their edges 146. In such an embodiment, to allowthe drug formulation retained within the reservoir 138 to be deliveredto the microneedle assembly 136, the bottom layer 144 of the reservoir138 may define an opening or window 148 that is in fluid communicationwith the microneedle assembly 136. For example, as shown FIG. 8, thewindow 148 may be defined in the bottom layer 144 such that, when thereservoir 138 is positioned directly above microneedle assembly 136, thedrug formulation may be directed through the window 148 and along thetop surface of the microneedle assembly 136 (i.e., the top surface 44 ofthe support 42).

It should be appreciated that the drug formulation may be supplied tothe reservoir 138 in a variety of different ways. For example, inseveral embodiments, the drug formulation may be supplied via an inletopening 150 defined in the top layer 142 (or the bottom layer 144) ofthe reservoir 138. In such an embodiment, a suitable conduit, portand/or tube may be in fluid communication within both the inlet opening150 and a suitable drug source (e.g., a syringe containing the drugformulation) such that the drug formulation may be directed through theinlet opening 150 and into the reservoir 138. For example, as shown inFIGS. 6-8, a supply port 152 may include a bottom end 154 configured tobe secured/sealed to the reservoir 138 around the inlet opening 140 suchthat the drug formulation may be delivered to the inlet opening 150 viaa supply channel 156 defined through the bottom end 154. Additionally,as shown in FIG. 5, a top end 158 of the supply port 152 may beconfigured to extend through a port opening 160 defined in the upperhousing portion 114. As such, the top end 158 may be accessed by theuser or a healthcare professional to permit the drug formulation to beinjected into the supply port 152. Although not shown, the supply port152 may also be configured to include a one-way valve to allow the drugformulation to flow through the port 152 in the direction of thereservoir 138 (i.e., from the top end 158 to the bottom end 154) and toprevent the flow of such drug formulation in the opposite direction(i.e., from the bottom end 154 to the top end 158).

In other embodiments, the drug formulation may be supplied to thereservoir 138 using any other suitable means/method. For example, in oneembodiment, the reservoir 138 may be configured to be pre-filled orpre-charged prior to being assembled into the device 10.

Additionally, the disclosed device 110 may also include a rate controlmembrane 170 to slow down or otherwise control the flow rate of the drugformulation as it is released into the microneedle assembly 136.Specifically, as shown in FIG. 8, the rate control membrane 170 may beconfigured to be secured within the reservoir 138 around the perimeterof the reservoir window 148 such that the drug formulation passesthrough the rate control membrane 170 prior to exiting the reservoir 138via the window 148. However, in other embodiments, the rate controlmembrane 170 may be positioned between the bottom layer 144 of thereservoir 138 and the microneedle assembly 136 at the location of thewindow 148. It should be appreciated that the rate control membrane 170may generally be configured the same as or similar to the rate controlmembrane 70 described above, such as by being fabricated from anysuitable permeable, semi-permeable or microporous material(s) thatallows for the membrane 170 to control the flow rate of the drugformulation flowing between the reservoir 138 and the microneedleassembly 136.

Referring still to FIGS. 5-10, as indicated above, the device 110 mayalso include a bilateral pushing element 140 disposed within the centralregion 130 of the device 110. In general, the pushing element 140 maycomprise any suitable biasing mechanism and/or force application meansthat is configured to apply a continuous bilateral force (having both adownward component and an upward component) through the device 110 andagainst the user's skin 18. For example, as shown in the illustratedembodiment, the pushing element 140 comprises an expandable memberpositioned between the upper housing portion 114 and the reservoir 138.The expandable member may generally be configured to be in anun-expanded state (FIGS. 6 and 9), in which the member does not transmitany forces through the central region 130 of the device 100, and anexpanded or actuated state (FIGS. 7 and 10), in which the member expandsoutwardly so as to apply a continuous bilateral force through thecentral region 130. For example, as particularly shown in FIGS. 9 and10, the expandable member may be configured to define a first height 172when in the un-expanded state and a larger, second height 174 when inthe actuated state.

Such expansion may generally provide a means for the expandable memberto apply both a continuous downward force and a continuous upward forcethrough the central region 130 of the device 110. Specifically thedownward component of the force (indicated by the arrows 184 in FIG. 7)may be transmitted downward through the central region 130 (e.g.,through the reservoir 138) to the microneedle assembly 136 such that themicroneedles 48 of the assembly 136 extend through the central opening121 (FIG. 8) and are pressed into and maintained within the user's skin18. It will be appreciated that, in such an embodiment, fluid within thereservoir 138 will be pressurized as a result of the downward pressurecomponent exerted by the bilateral pushing element 140. Similarly, theupward component of the force (indicated by the arrows 186 in FIG. 7)may be transmitted upward through the central region 130 (e.g., throughthe support member 124) to the housing 112, thereby pushing the housing112 away from the user's skin. However, since the housing 112 isattached to the user's skin 18 around its outer periphery (i.e., at theouter region 132 of the device 110), such upward force may generally betransmitted through the housing 112 to the adhesive layer 122 so as toprovide an upward, tensioning force against the user's skin 118. Thus,as the microneedles 48 are pushed downward into the user's skin 18, theuser's skin 18 may be pulled upwards around the device's periphery,thereby tightening the skin 18 around the microneedle assembly 36 andenhancing the ease at which the microneedles 48 may be inserted into andmaintained within the user's skin 18.

As particularly shown in FIGS. 9 and 10, in several embodiments, theexpandable member may include an expandable material 176 (e.g.,compressed foam) vacuum sealed within a suitable outer covering orjacket 178. As such, the expandable member may be activated by releasingthe vacuum and allowing air to flow into the jacket 178. For example, asshown in the illustrated embodiment, a peel strip or removable tab 180may be used to activate the expandable member by exposing a jacketopening 182 defined in the jacket 178. Specifically, as shown in FIG. 9,the removable tab 180 may be initially positioned over the jacketopening 182 so as to seal the opening 182 and maintain the vacuum withinthe jacket 178. However, as the removable tab 180 is pulled or peeledaway from the opening (e.g., by pulling on an exposed end 188 of the tab109), the seal may be broken and air may flow into the jacket 178,thereby allowing the expandable material 176 contained therein to expandoutwardly. In such an embodiment, a portion of the tab 180 may beconfigured to extend through a corresponding opening or slot 190 definedin the housing 112 to allow the tab 180 to be pulled or peeled away fromthe opening 182 by the user. It should be appreciated that the jacket178 may be stretchable, elastic, over-sized and/or may have any othersuitable configuration that allows for the expansion of the expandablematerial 176 contained therein.

In alternative embodiments, the vacuum contained within the jacket 178may be released using any other suitable activation means. For example,in another embodiment, a push button or other component may beconfigured to be pressed such that a pin, needle or other penetratingmechanism penetrates the jacket 178, thereby creating an aperture andreleasing the vacuum.

Additionally, it should be noted that, since the reservoir 138 isconfigured as a flexible bladder, the reservoir 138 may be pressurizedby the downward force applied by the pushing element 140. As such, thepressure of the drug formulation contained within the reservoir 138 maybe increased, thereby facilitating the flow of the formulation from thereservoir 138 to the microneedle assembly 136.

As indicated above, in addition to having a central region 30, 130 andan outer region 32, 132, the disclosed devices 10, 110 may also includeintermediate region 34, 134 defined between and separating the centraland outer regions 30, 130, 32, 132. In several embodiments, theintermediate regions 34, 134 of the devices 10, 110 may correspond toareas along which the device(s) 10, 110 do not contact the user's skin18. For example, as shown in FIGS. 2 and 3, the intermediate region 34of the device 10 may correspond to the open space defined underneath thehousing 12 between the adhesive layer 22 and the footprint defined bythe microneedle assembly 36, the reservoir 38 and the pushing element40. Similarly, as shown in FIGS. 6 and 7, the intermediate region 134 ofthe device 110 may correspond to the open space defined underneath thehousing 112 between the adhesive layer 122 and the footprint defined bythe microneedle assembly 136 and the pushing element 140. Thus, unlikethe central and outer regions wherein forces are transmitted through themicroneedle assemblies 36, 136 and adhesive layers 22, 122,respectively, to the user's skin 18, substantially no or no forces maybe transmitted through the intermediate regions 34, 134 to the user'sskin 18. As such, in several embodiments, a width 192 of theintermediate regions 34, 134 may be selected such that the downwardforce applied to the skin 18 through central regions 30, 130 and theupward force applied to the skin 18 through the outer regions 34, 134are sufficiently spaced apart from one another. For example, in oneembodiment, the width of the intermediate regions 34, 134 may range fromabout 0.5 millimeters (mm) to about 15 mm, such as from about 1 mm toabout 10 mm or from about 2 mm to about 5 mm and any other subrangestherebetween.

The dissociation or functional separation of the lower housing 116 andthe microneedle assembly 136 allows the two elements to moveindependently of one another as well as have transmitted to themsubstantially opposed components of force. Further, the superimpositionof the microneedle assembly 136, pushing element 140 and upper housing114 allows for the simultaneous application of a continuous upward forceto the lower housing 116 (e.g. via the upper housing 114) and acontinuous downward force to the microneedle assembly 136. However, itwill be appreciated that to effectively allow the independenttransmission of these generally opposing forces it will be appreciatedthat the pushing element 140 and lower housing 116 should also bedissociated or functionally separated from one another.

Additionally, it should be appreciated that, in several embodiments, theconfiguration of the disclosed pushing elements 40, 140 (e.g., thespring constant of the spring or the expansion constant of theexpandable member) may be selected such that the constant forcetransmitted to the microneedle assemblies 36, 136 is sufficient to causethe microneedles 48 to penetrate the user's skin 18 and remain thereinduring delivery of the drug formulation. For example, in severalembodiments, the pushing elements 40, 140 may be configured such thatthe upward and downward components of the force applied through thedevices 10, 110 ranges from about 0.1 Newtons (N) to about 20 N, such asfrom about 0.15 N to about 10 N or from about 0.25 N to about 5 N andall other subranges therebetween.

It should also be appreciated that, in alternative embodiments of thepresent subject matter, the pushing element 40, 140 may comprise anyother suitable element and/or member capable of providing a continuousbilateral force. For example, in one embodiment, the pushing element 40,140 may comprise a mechanical actuator, such as a solenoid-activatedcylinder or any other suitable actuator, positioned within the housing12, 112. In a further embodiment, the pushing element 40, 140 maycomprise a threaded bolt or screw that is configured to be screwed intothe housing 12, 112 so as to mechanically apply the continuous bilateralforce through the device 10, 110. Still further, a bladder or otherelement may be expanded with air pressure such as via a pump or othermechanism.

Moreover, it should be appreciated that the skin attachment means (e.g.,adhesive layers 22, 122) may generally be configured to define anysuitable width 194 so as to provide a sufficient surface area fortransferring the upward component of the force to the user's skin 18.For example, in several embodiments, the width 194 of the skinattachment means may range from about 5 millimeters (mm) to about 30 mm,such as from about 5 mm to about 25 mm or from about 10 mm to about 25mm and any other subranges therebetween.

As indicated above, the present subject matter is also directed to amethod for transdermally delivering a drug formulation. The method maygenerally include positioning a transdermal drug delivery device 10, 110adjacent to skin 18 and applying, with a pushing element 40, 140, acontinuous bilateral force having a downward component transmittedthrough a microneedle assembly 36, 136 of the device 10, 110 and anupward component transmitted through skin attachment means 22, 122 ofthe device 10, 110.

This written description uses examples to disclose the invention,including the best mode, and also to enable any person skilled in theart to practice the invention, including making and using any devices orsystems and performing any incorporated methods. The patentable scope ofthe invention is defined by the claims, and may include other examplesthat occur to those skilled in the art. Such other examples are intendedto be within the scope of the claims if they include structural elementsthat do not differ from the literal language of the claims, or if theyinclude equivalent structural elements with insubstantial differencesfrom the literal languages of the claims.

1. A transdermal drug delivery device comprising: a housing including anupper housing portion and a lower housing portion, the lower housingportion defining a bottom surface including skin attachment means forreleaseably attaching the lower housing portion to skin of a user, theupper housing portion at least partially surrounding a central region ofthe device; a microneedle assembly disposed within the central region; areservoir disposed within the central region, the reservoir being influid communication with the microneedle assembly; and a pushing elementdisposed above the microneedle assembly within the central region, thepushing element being configured to provide a continuous bilateral forcehaving a downward component transmitted through the microneedle assemblyand an upward component transmitted through the skin attachment means.2. The transdermal drug delivery device of claim 1, wherein thereservoir is disposed between the microneedle assembly and the pushingelement, the downward component of the continuous bilateral force beingtransmitted through the reservoir to the microneedle assembly.
 3. Thetransdermal drug delivery device of claim 2, wherein the reservoir isconfigured as a flexible bladder.
 4. The transdermal drug deliverydevice of claim 3, wherein the downward component of the continuousbilateral force pressurizes a drug fbrmulation contained within thereservoir.
 5. The transdermal drug delivery device of claim 2, whereinthe reservoir is configured as a rigid member and contains a drugformulation in the form of a fluid.
 6. The transdermal drug deliverydevice of claim 5, wherein the downward component of the continuousbilateral force is transmitted through the microneedle assembly withoutincreasing the pressure of the drug formulation contained within thereservoir.
 7. The transdermal drug delivery device of claim 1, whereinan outer region of the device is defined at the interface between theskin attachment means and the bottom surface of the lower housingportion, wherein the central region is defined by the footprint of themicroneedle assembly and the pushing element, wherein the downwardcomponent of the continuous bilateral force is transmitted through thecentral region to the microneedle assembly and the upward component ofthe continuous bilateral force is transmitted through the outer regionto the skin attachment means.
 8. (canceled)
 9. The transdermal drugdelivery device of claim 7, further comprising an intermediate regiondefined underneath the housing and separating the central and outerregions, wherein neither the downward component nor the upward componentof the continuous bilateral force is transmitted through theintermediate region.
 10. The transdermal drug delivery device of claim1, wherein the microneedle assembly is configured to move relative tothe housing when the downward component of the continuous bilateralforce is applied by the pushing element.
 11. The transdermal drugdelivery device of claim 1, wherein the pushing element comprises aspring compressed between the upper housing portion and the reservoir.12. The transdermal drug delivery device of claim 11, further comprisinga plunger disposed above the reservoir, the spring being compressedbetween the upper housing portion and the plunger.
 13. (canceled) 14.The transdermal drug delivery device of claim 1, wherein the pushingelement comprises an expandable member positioned between the upperhousing portion and the reservoir.
 15. The transdermal drug deliverydevice of claim 14, wherein the expandable member comprises anexpandable material vacuum sealed within a jacket.
 16. (canceled) 17.(canceled)
 18. A transdermal drug delivery device comprising: an upperhousing attached to a lower housing defining a cavity, the lower housingdefining a bottom surface including skin attachment means for releasablyattaching the lower housing to skin of a user; the lower housingdefining an opening and surrounding a microneedle assembly, the deviceconfigured such that the lower housing is dissociated from themicroneedle assembly; a reservoir disposed within the cavity and beingin fluid communication with the microneedle assembly; and a pushingelement disposed within the cavity between the microneedle assembly andthe upper housing, the pushing element being configured so as to bedissociated from the lower housing and provide (i) a continuous forcehaving a downward component, dissociated from the upper and lowerhousings, transmitted via the microneedle assembly towards the skin of auser, (ii) a continuous force having an upward component, dissociatedfrom the microneedle assembly, transmitted to the lower housing.
 19. Thetransdermal drug delivery device of claim 18, wherein the device furtherincludes a rigid member disposed between the upper housing and thepushing element.
 20. The transdermal drug delivery device of claim 18,wherein the reservoir comprises a rigid material and is positionedwithin the cavity between the pushing element and the microneedleassembly.
 21. The transdermal drug delivery device of claim 18, whereinthe pushing element is actuatable and comprises, prior to actuation, acompressed member.
 22. The transdermal drug delivery device of claim 18,wherein a top portion of the pushing element extends through an openingdefined in the upper housing, the top portion being movable relative tothe upper housing, wherein application of a downward force on the topportion transmits a further downwardly force against the microneedleassembly.
 23. A method for transdermally delivering a drug formulation,the method comprising: positioning a transdermal drug delivery deviceadjacent to skin, wherein the transdermal drug delivery devicecomprises: a housing including an upper housing portion and a lowerhousing portion, the lower housing portion defining a bottom surfaceincluding skin attachment means for releaseably attaching the lowerhousing portion to skin of a user, the upper housing portion at leastpartially surrounding a central region of the device; a microneedleassembly disposed within the central region; a reservoir disposed abovethe microneedle assembly within the central region, the reservoir beingin fluid communication with the microneedle assembly; and a pushingelement disposed above the microneedle assembly within the centralregion; and attaching the housing to the skin via the skin attachmentmeans; applying, with the pushing element, a continuous bilateral forcethrough the transdermal drug delivery device having a downward componenttransmitted through the microneedle assembly and an upward componenttransmitted through the skin attachment means; and delivering the drugformulation from through the microneedle assembly and into or throughthe skin.
 24. (canceled)
 25. (canceled)
 26. (canceled)
 27. (canceled)28. The method of claim 23, wherein applying the continuous bilateralforce comprises applying the continuous bilateral force with a springcompressed between the upper housing portion and the reservoir orapplying the continuous bilateral force with an expandable memberpositioned between the upper housing portion and the reservoir. 29.(canceled)
 30. (canceled)